Chronic high-dose glycine nutrition: Effects on rat brain cell morphology

Background: Facilitation of N-methyl-D-aspartate (NMDA) receptor-mediated n eurotransmission via administration of glycine site agonists of the NMDA re ceptor (e.g., glycine, D-serine), and glycine transport inhibitors may repr esent an innovative pharmacologic strategy in schizophrenia; however, given the potential involvement of NMDA receptors in the neurotoxicity of excita tory amino acids, possible neurotoxic effects of glycinergic compounds need to be explored. Furthermore, studying brain adaptations to chronic adminis tration of glycine site agonists may provide insights into the therapeutic mechanisms of these drugs. Methods: Adult rats were randomized to one of three nutritional regimes (no glycine supplementation, 1 g/kg/day, or 5 g/kg/day glycine supplementation ) and to one of three treatment durations (1, 3, or 5 months). Serum glycin e and serine levels at sacrifice and brain sections were examined using his tologic markers of neurodegeneration (cresyl violet and silver impregnation staining) and immunohistochemical staining of glial fibrillary acidic prot ein, microtubule-associated protein, and neurofilament 200. To explore addi tional neural adaptations to high-dose glycine treatment, immunostaining wa s also performed for class B, N-type Ca2+ channels. Results: Serum glycine levels increased dose dependently during glycine nut rition, whereas serine levels were not changed. In hippocampal dentate gyru s, the percentage of hypertrophied astrocytes transiently increased at 1 mo nth. At 3 and 5 months of glycine treatment, the density of class B, N-type Ca2+ channels was reduced in parietal cortex and hippocampus. No evidence of neuronal or glial cell excitotoxic damage or degeneration was registered at either of the treatment intervals studied. Conclusions: These findings demonstrate for the first time that in vivo adm inistration of high-dose glycine may induce brain morphological changes wit hout causing neurotoxic effects. A reduction in density of class B, N-type Ca2+ channels in specific brain regions may represent one general adaptatio n to long-term, high-dose glycine treatment. (C) 2001 Society of Biological Psychiatry.